NO149957B - PROCEDURE FOR PREPARING 4- (6`-METOXY-2`-NAPHYL) BUTAN-2-ON - Google Patents

Abstract

Process for the preparation of 4- (6-methoxy-2-naphthyl) butan-2-one.

Description

The invention relates to a process for the production of 4-(6<1->methoxy-2'-naphthyl)butan-2-one.

British patent 1,474,377 discloses, among other things, that 4-(6'-methoxy-2'-naphthyl)butan-2-one possesses useful anti-inflammatory activity. A particularly preferred method has now been discovered which can be used for the production of this compound with a particularly good yield. This method is characterized by hydrogenation of a compound of formula (I): where X and Y are each hydrogen atoms or together form a double bond between the carbon atoms to which they are linked; and R is a benzyl or substituted benzyl group with formula (a), (b) or (c),

where R 1 and R 2 independently of each other are hydrogen or halogen atoms or lower alkyl, lower alkoxy or nitro, and the hydrogenation takes place in an organic solvent.

Any substituent R 1 or R 2 present on a phenyl ring is preferably in the para or meta position. Halogen atoms are more appropriately bromine or chlorine atoms. In general, no more than one substituent R 1 or R 2 is present on the phenyl group.

Particularly suitable groups R include benzyl, p-methoxy-1 benzyl, p-bromobenzyl, p-methylbenzyl and p-chlorobenzyl.

One preferred group R is the benzyl group.

The hydrogenation of the compound of formula (I) can be carried out using a low, medium or high hydrogen pressure, e.g. from 0.5 to 4 atm. hydrogen, but in general, to prevent over-reduction, it is preferred to use a pressure of 0.9-1.5 atm. hydrogen, e.g. 1 atm. Print.

The hydrogenation will be carried out in the presence of a catalyst, e.g. a noble metal catalyst, e.g. palladium, which is preferred. Suitable forms of palladium catalysts include palladium on charcoal, palladium on barium sulfate, or palladium on calcium carbonate. Other noble metal catalysts which may be used include rhodium, e.g. rhodium on aluminum oxide. Platinum is not normally preferred.

Suitable solvents for the reaction include lower alcohols, esters and halohydrocarbons and ketone solvents, e.g. methyl isobutyl ketone or acetone. Particularly suitable solvents include esters, e.g. methyl acetate and ethyl acetate of which ethyl acetate is preferred.

The reaction can be carried out at reduced, ambient or elevated temperature, e.g. 0° to 35°C, and preferably at ambient temperature.

As soon as the reaction is over (e.g. determined by TLC or cessation of hydrogen uptake) the desired compound can be obtained by filtering off the catalyst and removing the solvent, e.g. by evaporation under reduced pressure.

If desired, the thus obtained compound can be further purified by recrystallization, e.g. from aqueous ethanol.

The hydrogenation of the compound of formula (I) is preferably carried out on a compound where X and Y represent a double bond together with the C-C bond present, on the basis of the convenient preparation of such compounds by reacting 6-methoxy-2-naphthaldehyde with a compound of formula

(III):

where R is as defined for formula (I).

The advantages of the synthesis according to the invention over the process using non-hydrogenolizable esters include (a) higher overall yields; (b) one less reaction step, which means less handling of compounds and apparatus and less opportunity for the formation of contaminants, and (c) efficient preparation.

The following examples illustrate the invention, but first a comparative example is reproduced.

Comparative example

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one using ethyl acetoacetate

6-Methoxy-2-naphthaldehyde (93.0 g, 0.5 mol), ethyl acetoacetate (71.5 g, 0.55 mol), cyclohexane (1.0 L), piperidine (5.0 mL), and phenylacetic acid ( 1.5 g) was heated under reflux for 22 h, water being removed using a Dean-Stark apparatus. Solvent was removed under reduced pressure to give crude 3-ethoxycarbonyl-4-(6'-methoxy-2<1->naphthyl)but-3-en-2-one (164.8 g) as a viscous oil that was used directly for the next step.

The viscous oil (162.9 g) in ethanol (1050 mL) was hydrogenated at room temperature and atmospheric pressure in the presence of 10% palladium on charcoal (15.0 g). After 5 1/2 hours the hydrogen uptake was complete and the catalyst was filtered off, washed with 100 ml of ethanol and the ethanol filtrates containing 3-ethoxycarbonyl-4-(6<1->methoxy-2<1->naphthyl)butane-2- on was used in the next step.

90% of the above filtrate (ie containing 0.45 mol of product assuming 100% conversion) (1200 mL) and 5N HCl (470 mL) were refluxed for 7 hours. Removal of ethanol under reduced pressure gave a leather colored solid which was dissolved in 1.0 L of ethyl acetate. The aqueous layer was separated and washed with more ethyl acetate (100 mL). The combined organic solutions were washed with sodium bicarbonate solution to pH 8

(800 ml), water and dried (Na 2 SO 4 ).

Removal of solvent under reduced pressure gave a leather-colored, oily solid (103.6 g) which was crystallized from 80% ethanol/water (588 mL) and then ethanol (275 mL) to give 4-(6<1 ->methoxy-2<1->naphthyl)-butan-2-one (55.9 g, 54.5%) m.p. 80.5-81°.

Reactions on a larger scale (with 27 mol of 6-methoxy-2-naphthaldehyde) have resulted in much lower total yields (37-41%) of the final product.

Example 1

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one using benzyl acetoacetate

Source material

6-Methoxy-2-naphthaldehyde (37.2 g, 0.2 mol), benzyl acetoacetate (40.0 g, 0.21 mol), cyclohexane (500 mL) and piperidinium acetate (2.0 g) were refluxed for 4 h, as water was removed with a Dean-Stark apparatus. Ether (250 mL) was added and the mixture cooled to 5° for 16 h to give 3-benzyloxycarbonyl-4-(6'-methoxy-2<1->naphthyl)but-3-en-2-one (58 .0 g, 80.6 %) m.p. 88-90° in the form of a yellow solid. This was not purified further, but was used directly in the next step.

3-Benzyloxycarbonyl-4-(6<1->methoxy-2'-naphthyl)but-3-en-2-one (58.0 g) was shaken with 10% palladium charcoal (4.0 g) in 500 ml ethyl acetate under hydrogen until the reaction was complete. Removal of catalyst by filtration followed by evaporation of the filtrate gave a white solid (36.0 g) which was recrystallized from 80% ethanol/water (200 mL) to give 4-(6*-methoxy-2' -naphthyl)butan-2-one [30.6 g, 83.3% (total yield from aldehyde 6 7.1%] mp 81°.

Reactions on a larger scale (with 20 mol of 6-methoxy-2-naphthaldehyde) maintained the overall yield of 67% final product.

Example 2

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one

The hydrogenation described in Example 1 was repeated using the alternative solvents methyl acetate, acetone and methyl isobutyl ketone (MIBK). Hydrogenation was carried out until the absorption was complete. The results were as follows:

Example 3

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one

The hydrogenation described in Example 1 was repeated using the alternative catalyst 5% rhodium on alumina. It was found that the theoretical uptake of hydrogen required 28 hours and that the yield achieved was 75%.

Example 4

Production of starting material

p-methylbenzylacetoacetate (18.0 g, 0.0874 mol), 6-methoxy-2-naphthaldehyde (14.8 g, 0.0796 mol), cyclohexane (200 mL) and a catalytic amount of piperidinium acetate (0.8 g ) were refluxed together for 2.5 h and the water collected in a Dean and Stark receiver. 170 ml of ether were added, the mixture was cooled to -5°, and 10.7 g of the compound 3-p-methylbenzyloxycarbonyl-4-(6<1->methoxy-2'-naphthyl)but-3-en- 2-on (compound A) in 36% yield. Further yields were isolated by cooling and by concentration and crystallization from ether so that a total of 22.6 g of compound A was finally obtained in 75.9% yield, in the form of a yellow solid, m.p. 78-80°.

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one

Compound A (5 g, 0.0134 mol), 10% palladium on charcoal (0.25 g) and ethyl acetate (30 ml) were shaken together under a hydrogen atmosphere until hydrogen uptake had subsided. Removal of the catalyst by filtration and the solvent by evaporation gave a white solid which was recrystallized from ethanol (15 ml) to give a total yield of 2.6 g of 4-(6'-methoxy-2< 1->naphthyl)butan-2-one (85.3%) in the form of a white solid, m.p. 78.5-80°. The overall yield from 6-methoxy-2-naphthaldehyde to 4-(6',methoxy-2'-naphthyl)butan-2-one using p-methylbenzylacetoacetate was 64.7%.

[p-Methylbenzylacetoacetate was prepared as follows: Ethyl acetoacetate (22.5 g, 0.173 mol) and p-methylbenzyl-. alcohol (18.3 g, 0.15 mol) was heated together at ca. 200°

and the liberated ethanol collected by distillation. The reaction mixture was then fractionally distilled, the final fraction boiling with a peak temperature of 118-122° at 1.0 mmHg being p-methylbenzyl acetoacetate. (Yield 26g)].

Example 5

Production of starting material

p-Methoxybenzylacetoacetate (25 g 0.1126 mol), 6-methoxy-2-naphthaldehyde (18.6 g 0.1 mol), cyclohexane (200 mL)

and piperidinium acetate (1 g) were refluxed together for 1.5 h and the water collected in a Dean and Stark receiver.

200 ml of ether was added, and the precipitated oil was allowed to crystallize overnight to give 31 g (79.5%) of 3-p-methoxybenzyl-oxycarbonyl-4-(6<1->methoxy-2<1-> naphthyl)but-3-en-2-one (compound A) in the form of a yellow solid, m.p. 93.5-95.5°.

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one

5 q of compound A was hydrogenated as indicated in Example 4 to give 2.3 g, (78.7%) of 4-(6'-meth-oxy-2'-naphthyl)-butan-2-one in the form of a white solid, m.p. 78.5-80°.

The overall yield from 6-methoxy-2-naphthaldehyde to 4-(6'-methoxy-2'-naphthyl)butan-2-one using p-methoxybenzylacetoacetate was 62.6%.

The [p-methoxybenzylacetoacetate was prepared on

the following way:

p-Methoxybenzyl alcohol (27.6 g, 0.2 mol) and ethyl acetoacetate (32 g, 0.246 mol) were heated together to approx.

190° and the ethanol thus formed collected by distillation. The reaction mixture was fractionally distilled and p-methoxybenzylacetoacetate collected at a peak temperature of 126-132° and a vacuum of 0.3 mmHg. Yield: 39 g (87.7%)].

Example 6

Production of starting material

Benzhydrylacetoacetate (9 g, 0.0336 mol), 6-methoxy-2-naphthaldehyde (5 g, 0.0269 mol), cyclohexane (80 mL) and piperidinium acetate (0.26 g) were refluxed together for 1.5 h and the water collected in a Dean and Stark receiver. 60 ml of ether was added and the mixture cooled to 0° to give 9.4 g (80%) of benzhydryloxycarbonyl-4-(6<1->methoxy-2-naphthyl)-but-3-en-2- on (compound B) in two portions, m.p. 124-126°.

Preparation of 4-(6'-methoxy-2'-naphthyl)butan-2-one

5 g (0.0115 mol) of compound B was hydrogenated as indicated in Example 4, so that 2.1 g (80.3%) of 4-(6'-methoxy-2-naphthyl)butane-2- on in the form of a white solid, m.p. 79-80.5°. Total yield from 6-methoxy-2-naphth-<!>. aldehyde to 4-(6'-methoxy-2-naphthyl)butan-2-one using benzhydrylacetoacetate is 64.2%.

[The benzhydrylacetoacetate was prepared as follows:

Benzhydrol (20 g, 0.1087 mol) and ethyl acetoacetate

(13 g, 0.1 mol) were heated together to 170° and the ethanol thus formed removed by distillation. Fractional distillation at 1.0 mmHg gave 10.5 g (39%) of benzhydrylacetoacetate as a colorless liquid which later solidified, m.p. 44-54°].

Claims (5)

1. Process for the production of 4-(6'-methoxy-2'-naphthyl)-butan-2-one, characterized by hydrogenating a compound of formula (I): where X and Y mean hydrogen or together and with the C-C bond present constitute a double bond and R is benzyl or substituted benzyl of formula where R' 1 and R 2 independently of each other mean hydrogen, halogen, lower alkyl, lower alkoxy, or nitro, in an organic solvent. 2. Method as stated in claim 1, characterized in that a compound is hydrogenated where R is a benzyl group. 3. Method as stated in claim 1 or 2, characterized in that a compound of formula (I) is used where X and Y together and with the present C-C bond form a double bond. 4. Method as stated in any one of claims 1 to 3, characterized in that the hydrogenation is carried out using a hydrogen pressure of 0.9-1.5 atm. in the presence of a noble metal catalyst. 5. Method as stated in claim 4, characterized in that palladium is used as metal.